Microbial sensing mechanisms are critical to shaping an effective immune response to invading pathogens. Understanding the pathways in place to recognize microbial pathogens is of great interest to human health and may promote development of treatments to protect against infectious diseases and to control opportunistic infections in immunocompromised patients. The Toll-like receptors (TLRs) are sensing molecules that respond to conserved molecular patterns in microbial proteins and nucleic acids. The role of TLRs in viral sensing during cytomegalovirus (CMV) infection has recently been investigated. Cytomegalovirus is a leading opportunistic pathogen in immunocompromised patients. Studies using murine CMV have demonstrated compartmental differences in TLR requirements for viral sensing. TLR9, which responds to viral DNA within the endosomal compartment, is required in spleen but not liver to initiate innate immune responses. Studies proposed here aim to elucidate the role of other nucleic acid-sensing TLRs in liver viral recognition using mice deficient in the endoplasmic reticulum protein UNC93B. UNC93B null mice do not signal through the endosomal nucleic acid-sensing receptors TLR3, 7 and 9. Therefore, through CMV infection of UNC93B-deficient mice, the role of these three TLRs in initiating early liver antiviral immune responses will be evaluated. Specifically, the production of early innate cytokines and chemokines, as well as the recruitment of key innate effector leukocytes to the liver will be investigated during MCMV infection. Further, the effect of UNC93B-deficiency on viral replication and liver pathology will be determined. The overall goal is to more clearly determine whether nucleic acid-sensing TLR-dependent mechanisms are in place in the liver to initiate antiviral defenses using a model of MCMV infection. PUBLIC HEALTH RELEVANCE: The goal of proposed studies is to understand how the opportunistic pathogen murine cytomegalovirus is recognized by the host leading to effective antiviral immune responses. Understanding the mechanistic basis of these responses is critical to human health and provides the basis for developing specific antiviral therapies. This research is particularly relevant to promoting the health of AIDS patients, transplant recipients, and other immunosuppressed individuals who are highly susceptible to infection with this opportunistic virus.